Small tumors and large motion effects dampen treatment effect in IMPT
Intensity-modulated proton beam therapy (IMPT) has proven to be one of the most precise methods for targeting tumors with a sufficient radiation dose to kill the tumor, but there is a body of literature suggesting that tumor size and patient motion interact to affect radiation dose distribution. That notion has won new backing in a recent study that suggests that treatment of small tumors during respiratory-related tumor motion can suffer even with fractionation, particularly when irregular breathing patters are exhibited. This study evaluated the use of pencil-beam proton therapy as delivered to a two-dimensional ion chamber array placed in solid water on a unidimensional motion platform. The induced motion was based on sine and cosine waves produced in a pattern intended to mimic both sinusoidal and asymmetric breathing motions, respectively. Motion amplitudes of one half and one centimeter in this mechanism were expected to correspond with one and two centimeters of motion of maximum respiratory excursions, assuming a five-second fixed breathing cycle. The mock tumors were configured at three and 10 centimeters, which were placed at depths of one to five centimeters in water, and the test dosing scheme called for fractionations of 200 cGy at one, five, 10 and 15 fractionations. The authors said dose conformity and dose homogenieity were both more easily obtained when symmetric breathing patters were imposed on the test article compared to asymmetric breathing patterns, regardless of the number of fractionations. However, dose conformity and homogeneity were both more affected by motion when smaller tumors were evaluated. The authors said that motion effects are generally expected to even out over the course of multiple-fractionated treatment regimes, this might not hold for proton pencil beam scanning for smaller tumors when the patient’s breathing patters are asymmetrical. These findings are explained in more detail in the Journal of Applied Medical Physics.
Pancreatic cancer uses autophagy to hide from immune system
Researchers at New York University School of Medicine have demonstrated that pancreatic cancer cells specifically targeted their major histocompatibility complex class I (MHC-1) for destruction via autophagy as an immune evasion mechanism. MHC-1 molecules present antigens to the immune system, and some mutations in MHC-1 molecules are associated with resistance to checkpoint blockade inhibition. Pancreatic cancer is also resistant to checkpoint blockade, but the resistance-conferring MHC-1 mutations are rarely found in pancreatic tumors. The authors demonstrated that pancreatic tumor cells down-regulated their MHC-1 surface molecules by targeting for destruction by autophagy via the receptor NPR1. The team also found that “inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumor T cell responses and reduced tumor growth in syngeneic host mice,” as well as sensitizing mice to checkpoint blockade. The team published its findings in the April 23, 2020, issue of Nature.
NRF2 wakes sleeping tumor cells
Investigators at Duke University have delineated metabolic changes that could cause breast tumor cells to exit dormancy and resume proliferating. Dormancy is a troubling feature of certain tumor types, including breast tumors, that enables them to remain in a nondividing state for very long periods. Clinically, that translates into a relapse risk for breast cancer that declines over time, but remains elevated for decades after treatment. How tumor cells enter and exit dormancy remains poorly understood, but there are clearly major metabolic differences between dormancy and proliferation. The authors discovered that “Her2 downregulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor NRF2. NRF2 is activated during dormancy and in recurrent tumors in animal models and patients with breast cancer with poor prognosis.” Activation of NRF2 accelerated the recurrence of dormant tumors in animal models, while suppression of NRF2 could prevent recurrence. The team reported its results in the April 20, 2020, online issue of Nature Metabolism.
Cancer renders patients more susceptible to COVID-19
It may seem obvious that a diagnosis of cancer renders the patient’s immune system less able to fight off the SARS-CoV-2 virus, but a new paper confirms that notion in a study which suggests that lung and hematological cancers are conspicuous in this regard. This study of more than 100 patients diagnosed with both a cancer and COVID-19 treated in 14 centers in Wuhan, China, matched those outcomes with randomly selected COVID-19 patients who had not been diagnosed with any cancer. The patient-matching approach controlled for age and COVID symptoms, although there was a higher prevalence of “chest distress” in the study arm than in the control arm. The patients with both cancer and COVID-19 were more than twice as likely (hazard ratio of 2.34) than those with COVID only, while the hazard ratio for intensive care admission was 2.84 for the patients with both cancer and COVID-19. Even after adjusting for age, sex, smoking status and comorbidities, the dual-illness arm was more than twice as likely to die, and three times as likely to be admitted to the ICU. Mechanical ventilation was observed at 2.7 times the rate compared to controls as well. The death rates for patients with leukemia, lymphoma and myeloma were especially conspicuous at 33.3%, while patients with lung cancer perhaps not unexpectedly had a high death rate (18%, or four of 22 patients). Advanced cancers were also associated with worsening outcomes. This study appears in the April 28, 2020, online issue of Cancer Discovery.